血管紧张素II及血管紧张素II 1型受体拮抗剂对大鼠肝星状细胞增殖、收缩及胶原合成的影响
Effect of angiotensin II and angiotensin II type 1 receptor antagonist on the proliferation, contraction and collagen synthesis in rat hepatic stellate cells.
作者信息
Liu Jun, Gong Hao, Zhang Zhong-tao, Wang Yu
机构信息
Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
出版信息
Chin Med J (Engl). 2008 Jan 20;121(2):161-5.
BACKGROUND
Angiotensin II (Ang II) is a very important vasoactive peptide that acts upon hepatic stellate cells (HSCs), which are major effector cells in hepatic cirrhosis and portal hypertension. The present study was aimed to investigate the effects of Ang II and angiotensin II type 1 receptor antagonist (AT(1)RA) on the proliferation, contraction and collagen synthesis in HSCs.
METHODS
HSC-T6 rat hepatic stellate cell line was studied. The proliferation of the HSC cells was evaluated by MTT colorimetric assay while HSC DNA synthesis was measured by (3)H-thymidine incorporation. The effects of angiotensin II and AT(1)RA on HSCs contraction were studied by analysis of the contraction of the collagen lattice. Cell culture media were analyzed by RT-PCR to detect secretion of collagen I (Col I), collagen III (Col III) and transforming growth factor beta1 (TGF-beta1) by enzyme linked immunosorbent assay. HSC was harvested to measure collagen I, collagen III and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression.
RESULTS
Ang II ((1 x 10(-10) - 1 x 10(-4)) mol/L) stimulated DNA synthesis and proliferation in HSCs compared with untreated control cells. AT(1)RA inhibited angiotensin II induced proliferation of HSCs. A linear increase in the contractive area of collagen lattice correlated with the concentration of angiotensin II (1 x 10(-9) - 1 x 10(-5) mol/L) and with time over 48 hours. AT(1)RA blocks angiotensin II induced contraction of collagen lattice. Col I, Col III and TGF-beta1 levels of the Ang II group were higher than those of control group and this increase was downregulated by AT(1)RA. The mRNA expressions of Col I, Col III and TIMP-1 were higher in HSCs from the Ang II group than the control group and downregulated by AT(1)RA.
CONCLUSIONS
Angiotensin II increased DNA synthesis and proliferation of HSCs in a dose-dependent manner, stimulated the contraction of HSCs dose- and time-dependently. Angiotensin also promoted excretion of Col I, Col III and TGF-beta1 levels and stimulated Col I, Col III and TIMP-1 expression in HSCs. Angiotensin acts via the angiotensin II receptor because all of these effects are blocked by angiotensin II type 1 receptor antagonist.
背景
血管紧张素II（Ang II）是一种非常重要的血管活性肽，作用于肝星状细胞（HSCs），而肝星状细胞是肝硬化和门静脉高压症的主要效应细胞。本研究旨在探讨Ang II和血管紧张素II 1型受体拮抗剂（AT(1)RA）对肝星状细胞增殖、收缩和胶原合成的影响。
方法
研究HSC-T6大鼠肝星状细胞系。采用MTT比色法评估肝星状细胞的增殖，用（3）H-胸腺嘧啶核苷掺入法测量肝星状细胞DNA合成。通过分析胶原格子的收缩来研究血管紧张素II和AT(1)RA对肝星状细胞收缩的影响。通过RT-PCR分析细胞培养基，用酶联免疫吸附测定法检测I型胶原（Col I）、III型胶原（Col III）和转化生长因子β1（TGF-β1）的分泌。收获肝星状细胞以测量I型胶原、III型胶原和金属蛋白酶组织抑制剂-1（TIMP-1）mRNA的表达。
结果
与未处理的对照细胞相比，Ang II（（1×10(-10)-1×10(-4)）mol/L）刺激肝星状细胞的DNA合成和增殖。AT(1)RA抑制血管紧张素II诱导的肝星状细胞增殖。胶原格子收缩面积的线性增加与血管紧张素II的浓度（1×10(-9)-1×10(-5)mol/L）以及48小时内的时间相关。AT(1)RA阻断血管紧张素II诱导的胶原格子收缩。Ang II组的Col I、Col III和TGF-β1水平高于对照组，而这种增加被AT(1)RA下调。Ang II组肝星状细胞中Col I、Col III和TIMP-1的mRNA表达高于对照组，并被AT(1)RA下调。
结论
血管紧张素II以剂量依赖的方式增加肝星状细胞的DNA合成和增殖，剂量和时间依赖性地刺激肝星状细胞的收缩。血管紧张素还促进Col I、Col III和TGF-β1水平的排泄，并刺激肝星状细胞中Col I、Col III和TIMP-1的表达。血管紧张素通过血管紧张素II受体起作用，因为所有这些作用都被血管紧张素II 1型受体拮抗剂阻断。
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